SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication

Halder, Torrecilla, Burkhalter, Popović, Fielden, Vaz, Oehler, Pilger, Lessel, Wiseman, Singh, Vendrell, Fischer, Philipp, Ramadan (2019) SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication Nat Commun (IF: 16.6) 10(1) 3142

Abstract

The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient in SPRTN protease exhibit DPC-induced replication stress and genome instability, manifesting as premature ageing and liver cancer. Here, we provide a body of evidence suggesting that SPRTN activates the ATR-CHK1 phosphorylation signalling cascade during physiological DNA replication by proteolysis-dependent eviction of CHK1 from replicative chromatin. During this process, SPRTN proteolyses the C-terminal/inhibitory part of CHK1, liberating N-terminal CHK1 kinase active fragments. Simultaneously, CHK1 full length and its N-terminal fragments phosphorylate SPRTN at the C-terminal regulatory domain, which stimulates SPRTN recruitment to chromatin to promote unperturbed DNA replication fork progression and DPC repair. Our data suggest that a SPRTN-CHK1 cross-activation loop plays a part in DNA replication and protection from DNA replication stress. Finally, our results with purified components of this pathway further support the proposed model of a SPRTN-CHK1 cross-activation loop.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637133
http://www.ncbi.nlm.nih.gov/pubmed/31316063
http://dx.doi.org/10.1038/s41467-019-11095-y

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